This PrPmtA transgenic strain expresses mutant human A53T alpha-synuclein (SNCA). Homozygotes may be a useful model for early stages of Parkinson's Disease, in particular to study the mechanisms of striatal synaptic plasticity, and may become a useful tool to study mechanisms of LevoDopa-induced dyskinesia.
Georg Auburger, University Medical School
These transgenic mice express the mutant A53T human alpha-synuclein (SNCA) under the direction of the mouse prion protein promoter in nigrostriatal and corticostriatal projection neurons, but not local striatal neurons. The A53T mutation is associated with
early onset familial Parkinson's disease. Transgene expression levels are 1.5-2 fold greater than endogenous mouse gene expression levels. Homozygotes older than 6 months of age display progressively spontaneous vertical movement (rearing). At 7 months of age, dense alpha-synuclein immunoreactive resembling Lewy neurites is detected in the olfactory bulb. Ultrastructural examination of neurons reveals diffuse accumulation of human alpha-synuclein. A53T SCNA protein is detected in neuronal axons, dendrites, cell bodies, and nuclei throughout the CNS by immunohistochemical analysis (including: olfactory bulb, cerebral cortex, hippocampus, midbrain, pons, medulla oblongata). Mice 18 months of age and older display insoluble alpha-synuclein in nigrostriatal tissue together with an increase of 14-3-3 isoforms in striatum, elevated striatal dopamine levels, altered dopamine release, decreased transcript levels of the extraneural dopamine degradation enzyme COMT, upregulated striatal dopamine receptors, decreased postsynaptic dopamine response in Homer1 (homer homolog 1 (Drosophila)), Cb1 (cannabinoid receptor 1 (brain)) and Pde7b (phosphodiesterase 7B) transcript levels as well as impaired corticostriatal long term depression. Survival of homozygotes at 24 months of age is lower than survival of wildtype controls. Mice homozygous for the transgenic insert are viable, fertile, and normal in size.
A transgenic construct containing the entire translated portion of the mutant A53T human alpha-synuclein (SNCA) from position 22 to 515, driven by an ~3.5 kb fragment of the mouse prion protein promoter (Prnp), and polyadenylation signal sequence, was injected into fertilized FVB/N mouse eggs. Founder line A was subsequently established. The transgenic mice were then crossed to a targeted mutation strain on the 129 background. Upon arrival at The Jackson Laboratory, the double mutant mice were crossed to FVB/NJ (Stock No. 001800) at least once to establish the colony. The transgene was then separated from the double mutant by selective breeding to establish this strain.
|Expressed Gene||SNCA, synuclein alpha, human|
|Site of Expression|
|Allele Name||transgene insertion A, Georg Auburger|
|Allele Type||Transgenic (Inserted expressed sequence, Humanized sequence)|
|Allele Synonym(s)||A53T; PrPmtA; PrPmtB; Tg(Prnp-SNCA*A53T)BAub|
|Gene Symbol and Name||Tg(Prnp-SNCA*A53T)AAub, transgene insertion A, Georg Auburger|
|Promoter||Prnp, prion protein, mouse, laboratory|
|Expressed Gene||SNCA, synuclein alpha, human|
|Strain of Origin||FVB/N|
|Molecular Note||A construct containing the entire translated portion of human alpha-synuclein, SNCA from position 22 to 515, driven by an ~3.5 kb fragment of the mouse prion protein promoter, Prnp, was generated. The SNCA cDNA was followed by polyadenylation sequences derived from the 3' untranslated region of the boving growth hormone gene. This construct was microinjected into pronuclei of fertilized FVB/N ova.Transgenic protein expression was detected in the neuropil, with, more rarely, additional protein within neuronal cell bodies and neurites in the brain and motoneurons in the spinal cord. Two lines, A and B, were generated, have both been extensively studied, showing extremely similar phenotypes (J:86222, J:124976).|
|Mutations Made By|| |
Robert Nussbaum, University of California San Francisco
When maintaining a live colony, these mice can be bred as homozygotes. However, survival of homozygotes at 24 months of age is lower than survival of wildtype controls.
When using the FVB;129-Tg(Prnp-SNCA*A53T)AAub/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #017744 in your Materials and Methods section.
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